Heart Field Development

心田开发

• 批准号: 9045697
• 负责人: Takashi Mikawa
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045697
• 关键词: Anterior; Bilateral; Cardiac; Cell Death; Cell division; Cells; Coupled; Destinations; Development; Embryo; Embryonic Development; Gene Transfer Techniques; Genes; Genetic; Growth; Handedness; Health; Heart; Heart Atrium; Image; Individual; Label; Lateral; Lead; Left; Life; Mediating; Mesoderm; Modeling; Molecular; Monitor; Movement; Myocardial; Myocardium; Organ; Pacemakers; Pathway interactions; Pattern; Population; Positioning Attribute; Primitive Streaks; Process; Randomized; Research; Role; Series; Specific qualifier value; Testing; Time; Tissues; base; cardiogenesis; cell fate specification; daughter cell; embryo monitoring; gastrulation; intercalation; migration; novel; precursor cell

DESCRIPTION (provided by applicant): Project Summary During embryogenesis, organ precursors must be precisely positioned to allow the critical inductive tissue- tissue interactions which drive cell fate specification to occur. How heart field precursors are positioned during development, however, remains poorly understood. The current model assumes that all myocardial and endocardial cells arise from the primary and secondary (or anterior) heart fields (1¿HF and 2¿HF). We have recently found however that: (i) many cells of the atrial and atrioventricular junction myocardium, the pacemaker, inflow, and proepicardium do not originate in either HF; and (ii) surprisingly, they are derived from the lateral plate mesoderm (designated as "the tertiary HF (3¿HF)" hereafter) posterior to the 1¿HF and 2¿HF. Importantly, our preliminary study has revealed that: (iii) precursors of the 3¿HF as well as the 1¿HF and 2¿HF are among the first cells to form the primitive streak; (iv) they exit from the primitive streak bilaterally without crossing the embryonic midline and (v) migrate with little lateral cell intercalation until their arrival at each HF. Thus, an original position of HF precursor cells withn the PS predicts their defined destination within the left or right. Despite the importance of PS-origin for all three HFs, little is known about how the HF precursors populate to the defined position within the PS and how they migrate symmetrically to form the three HFs bilaterally. Further, our previous studies have identified that: (vi) the precursors of the 1¿HF and 2¿HF reside at the posterior end of the blastodisc; (g) individual precursor cells undergo an oriented cell division and generate a series of daughter cells that are aligned as an array along the embryonic AP axis of the primitive streak; (vii) midline cells of the primitive streak uniquely undergo cell death: and finally (viii) inhibition of the midline cell death results in randomizatio of heart looping. These findings lead to a novel model for heart field mesodermal patterning whereby oriented cell division in the PS coupled with midline cell death precisely position HF precursors prior to gastrulation. This proposal will test this model by determining: the origin and formation of three HFs from the primitive streak (Aim 1), the ability of a oriented cell division t drive precursors of individual HFs to defined domains within the primitive streak (Aim 2), and the regulatory role of midline cell death for defining the left and right migration pathways of HF precursors to form bilateral HFs (Aim 3). Taken together, the proposed study will provide the first understanding of how cardiac precursors gastrulate in amniotes, while establishing the importance of coordinated positioning in the primitive streak to ultimate cardiogenic fate.

描述（应用程序提供）：胚胎发生过程中的项目摘要，必须精确定位器官前体，以允许关键的电感组织相互作用 哪个驱动细胞命运规范发生。然而，在发育过程中，心脏场前体的位置如何保持不足。当前模型假定来自原发性和继发性（或前）心脏场（1？HF和2¿HF）的所有心肌和心内膜细胞。然而，我们最近发现：（i）心房和心房连接心肌的许多细胞，起搏器，流入和胸膜膜都不起源于任何HF； （ii）令人惊讶的是，它们源自侧板中胚层（称为“第三级HF（3？hf）”）后部的后部1 hf和2 hf。重要的是，我们的初步研究表明：（iii）3 hf以及1 hf和2？hf的前体是最早形成原始条纹的细胞之一； （iv）他们双侧从原始条纹退出而不越过胚胎中线，（v）迁移几乎没有侧向细胞插入，直到它们到达每个HF。这是HF前体单元格的原始位置，其ps可以预测其在左或右内定义的目的地。尽管PS-Origin对于所有三个HF都很重要，但对于HF前体如何填充PS内的定义位置以及它们如何对称迁移以双侧形成三个HFS。此外，我们以前的研究已经确定：（vi）1 hf和2 hf的前体居住在骨化轴的后端； （g）在定向细胞分裂下的单个前体细胞，并产生一系列的子细胞，这些细胞沿原始条纹的胚胎AP轴对齐为阵列； （vii）原始条纹的中线细胞独特地经历细胞死亡：最后（VIII）抑制中线细胞死亡会导致心脏循环的随机化。这些发现导致了心脏场中胚层模式的新型模型，在该模型中，PS中的定向细胞分裂与中线细胞死亡相结合，精确地位于HF前体的位置HF前体。该建议将通过确定来测试此模型：起源和 从原始条纹形成三个HF（AIM 1），即定向细胞分裂t驱动单个HFS在原始条纹内定义域的前体的能力（AIM 2），以及中线细胞死亡的调节作用在定义HF前体的左和右迁移途径以形成双层HF的左和右迁移途径（AIM 3）。综上所述，拟议的研究将首先了解心脏前体在羊水中如何胃肠道，同时确定原始条纹中协调定位对最终心源性命运的重要性。